Glaucoma is the leading cause of irreversible blindness in the world. Elevated intraocular pressure (IOP) is the most significant risk factor contributing to death of retinal ganglion cells (RGCs) and resulting visual field loss in primary open angle glaucoma (POAG). The current standard of care for glaucoma includes treatment with IOP- lowering medications delivered topically as eye drops. However, many patients continue to lose visual fields despite being on IOP-lowering drops. We have taken a comprehensive genetics approach to seek new drug targets that may address the limitations of current therapies. We have demonstrated that Cacna2d1 is specifically linked to high IOP both in mice and humans. We have also shown that a selective Cacna2d1 blocker exhibits potent IOP-lowering activity that can achieve a maximal IOP reduction >40% that does not return to baseline for ~33 hours when delivered by bioadhesive microemulsion. We have also determined that CACNA2D1 is localized to the CB, TM and RGCs, suggesting that inhibitors of this protein could both lower IOP and protect RGCs. Lastly, we have shown that the degree of IOP lowering is correlated with the gene haplotype, thus demonstrating the potential of tailoring treatment to a patient?s genetic profile. Our overall objective is to develop and validate one or more novel topical formulations to deliver the effective drugs to inhibit CACNA2D1 in a once daily topical formulation. This treatment strategy will reduce the burden to the patient, increase compliance and lead to better visual outcomes. Our central hypothesis is that a small molecule that targets CACNA2D1?when formulated in a topical microemulsion?will elicit an IOP-lowering response that is greater in amplitude and duration than other glaucoma medications. Overall strengths of this proposal include: 1) the combination of a strong interdisciplinary team; 2) the successful utilization of a genetics approach to identify a new drug target for blocking glaucoma-related increases in IOP and RGC death; 3) the potential for utilizing our novel drug for precision medicine and; 4) the development and optimization of an innovative IOP delivery strategy using an extended-release formulation. In this proposal, we provide proof-of-concept data and address key feasibility questions by establishing efficacy, pharmacodynamics, biocompatibility and biodistribution of our novel microemulsion treatment. We develop a novel topical once daily microemulsion formulation as a new glaucoma therapy; measure the movement of CACNA2D1 inhibitors across the cornea, determine pharmacokinetic movements in the eye and assess full- body biodistribution; establish the mechanism of action of CACNA2D1 inhibitors as glaucoma therapies; determine if the haplotype of Cacna2d1 influences the IOP-lowering response to our formulation(s); and prepare and submit an IND application to the FDA. These results will position us to proceed directly to a Phase II demonstration project in preparation for Phase III commercialization.